Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication. / Jones, Mathew J K; Gelot, Camille; Munk, Stephanie; Koren, Amnon; Kawasoe, Yoshitaka; George, Kelly A.; Santos, Ruth E; Olsen, Jesper V.; McCarroll, Steven A; Frattini, Mark G; Takahashi, Tatsuro S; Jallepalli, Prasad V.

In: Molecular Cell, Vol. 81, No. 3, 2021, p. 426-441.e8.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Jones, MJK, Gelot, C, Munk, S, Koren, A, Kawasoe, Y, George, KA, Santos, RE, Olsen, JV, McCarroll, SA, Frattini, MG, Takahashi, TS & Jallepalli, PV 2021, 'Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication', Molecular Cell, vol. 81, no. 3, pp. 426-441.e8. https://doi.org/10.1016/j.molcel.2021.01.004

APA

Jones, M. J. K., Gelot, C., Munk, S., Koren, A., Kawasoe, Y., George, K. A., Santos, R. E., Olsen, J. V., McCarroll, S. A., Frattini, M. G., Takahashi, T. S., & Jallepalli, P. V. (2021). Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication. Molecular Cell, 81(3), 426-441.e8. https://doi.org/10.1016/j.molcel.2021.01.004

Vancouver

Jones MJK, Gelot C, Munk S, Koren A, Kawasoe Y, George KA et al. Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication. Molecular Cell. 2021;81(3):426-441.e8. https://doi.org/10.1016/j.molcel.2021.01.004

Author

Jones, Mathew J K ; Gelot, Camille ; Munk, Stephanie ; Koren, Amnon ; Kawasoe, Yoshitaka ; George, Kelly A. ; Santos, Ruth E ; Olsen, Jesper V. ; McCarroll, Steven A ; Frattini, Mark G ; Takahashi, Tatsuro S ; Jallepalli, Prasad V. / Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication. In: Molecular Cell. 2021 ; Vol. 81, No. 3. pp. 426-441.e8.

Bibtex

@article{478d2704726f4fd7bfde8ef32eab39dc,
title = "Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication",
abstract = "Eukaryotic genomes replicate via spatially and temporally regulated origin firing. Cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK) promote origin firing, whereas the S phase checkpoint limits firing to prevent nucleotide and RPA exhaustion. We used chemical genetics to interrogate human DDK with maximum precision, dissect its relationship with the S phase checkpoint, and identify DDK substrates. We show that DDK inhibition (DDKi) leads to graded suppression of origin firing and fork arrest. S phase checkpoint inhibition rescued origin firing in DDKi cells and DDK-depleted Xenopus egg extracts. DDKi also impairs RPA loading, nascent-strand protection, and fork restart. Via quantitative phosphoproteomics, we identify the BRCA1-associated (BRCA1-A) complex subunit MERIT40 and the cohesin accessory subunit PDS5B as DDK effectors in fork protection and restart. Phosphorylation neutralizes autoinhibition mediated by intrinsically disordered regions in both substrates. Our results reveal mechanisms through which DDK controls the duplication of large vertebrate genomes.",
keywords = "Adaptor Proteins, Signal Transducing/genetics, Animals, Ataxia Telangiectasia Mutated Proteins/genetics, Cell Cycle Proteins/genetics, Checkpoint Kinase 1/genetics, DNA Replication/drug effects, DNA-Binding Proteins/genetics, Female, HCT116 Cells, HEK293 Cells, HeLa Cells, Humans, Phosphorylation, Protein Kinase Inhibitors/pharmacology, Protein-Serine-Threonine Kinases/genetics, Replication Origin, S Phase Cell Cycle Checkpoints, Substrate Specificity, Time Factors, Transcription Factors/genetics, Xenopus laevis",
author = "Jones, {Mathew J K} and Camille Gelot and Stephanie Munk and Amnon Koren and Yoshitaka Kawasoe and George, {Kelly A.} and Santos, {Ruth E} and Olsen, {Jesper V.} and McCarroll, {Steven A} and Frattini, {Mark G} and Takahashi, {Tatsuro S} and Jallepalli, {Prasad V}",
year = "2021",
doi = "10.1016/j.molcel.2021.01.004",
language = "English",
volume = "81",
pages = "426--441.e8",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "3",

}

RIS

TY - JOUR

T1 - Human DDK rescues stalled forks and counteracts checkpoint inhibition at unfired origins to complete DNA replication

AU - Jones, Mathew J K

AU - Gelot, Camille

AU - Munk, Stephanie

AU - Koren, Amnon

AU - Kawasoe, Yoshitaka

AU - George, Kelly A.

AU - Santos, Ruth E

AU - Olsen, Jesper V.

AU - McCarroll, Steven A

AU - Frattini, Mark G

AU - Takahashi, Tatsuro S

AU - Jallepalli, Prasad V

PY - 2021

Y1 - 2021

N2 - Eukaryotic genomes replicate via spatially and temporally regulated origin firing. Cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK) promote origin firing, whereas the S phase checkpoint limits firing to prevent nucleotide and RPA exhaustion. We used chemical genetics to interrogate human DDK with maximum precision, dissect its relationship with the S phase checkpoint, and identify DDK substrates. We show that DDK inhibition (DDKi) leads to graded suppression of origin firing and fork arrest. S phase checkpoint inhibition rescued origin firing in DDKi cells and DDK-depleted Xenopus egg extracts. DDKi also impairs RPA loading, nascent-strand protection, and fork restart. Via quantitative phosphoproteomics, we identify the BRCA1-associated (BRCA1-A) complex subunit MERIT40 and the cohesin accessory subunit PDS5B as DDK effectors in fork protection and restart. Phosphorylation neutralizes autoinhibition mediated by intrinsically disordered regions in both substrates. Our results reveal mechanisms through which DDK controls the duplication of large vertebrate genomes.

AB - Eukaryotic genomes replicate via spatially and temporally regulated origin firing. Cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK) promote origin firing, whereas the S phase checkpoint limits firing to prevent nucleotide and RPA exhaustion. We used chemical genetics to interrogate human DDK with maximum precision, dissect its relationship with the S phase checkpoint, and identify DDK substrates. We show that DDK inhibition (DDKi) leads to graded suppression of origin firing and fork arrest. S phase checkpoint inhibition rescued origin firing in DDKi cells and DDK-depleted Xenopus egg extracts. DDKi also impairs RPA loading, nascent-strand protection, and fork restart. Via quantitative phosphoproteomics, we identify the BRCA1-associated (BRCA1-A) complex subunit MERIT40 and the cohesin accessory subunit PDS5B as DDK effectors in fork protection and restart. Phosphorylation neutralizes autoinhibition mediated by intrinsically disordered regions in both substrates. Our results reveal mechanisms through which DDK controls the duplication of large vertebrate genomes.

KW - Adaptor Proteins, Signal Transducing/genetics

KW - Animals

KW - Ataxia Telangiectasia Mutated Proteins/genetics

KW - Cell Cycle Proteins/genetics

KW - Checkpoint Kinase 1/genetics

KW - DNA Replication/drug effects

KW - DNA-Binding Proteins/genetics

KW - Female

KW - HCT116 Cells

KW - HEK293 Cells

KW - HeLa Cells

KW - Humans

KW - Phosphorylation

KW - Protein Kinase Inhibitors/pharmacology

KW - Protein-Serine-Threonine Kinases/genetics

KW - Replication Origin

KW - S Phase Cell Cycle Checkpoints

KW - Substrate Specificity

KW - Time Factors

KW - Transcription Factors/genetics

KW - Xenopus laevis

U2 - 10.1016/j.molcel.2021.01.004

DO - 10.1016/j.molcel.2021.01.004

M3 - Journal article

C2 - 33545059

VL - 81

SP - 426-441.e8

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 3

ER -

ID: 259631737